Our long-term goal is to understand the tissue-specific function of BRCA1 and how its impairment leads to breast tumorigenesis. In the past decades, others and we have focused on elucidating roles of BRCA1 in DNA damage response and cell cycle checkpoint control. Although this DNA damage response function of BRCA1 is important for tumor suppression, it fails to fully explain how an aberrant function of BRCA1 is correlated with accelerated growth and progression of hereditary and sporadic breast cancer as well as impairment of mammary gland differentiation. Emerging evidence suggests that BRCA1 may serve as a transcriptional regulator for a diverse group of genes responsible for proliferation and differentiation of mammary epithelial cells. A cross interaction between BRCA1 and nuclear hormone receptors including estrogen and progesterone receptors provides a potential window to address the tissue (mammary epithelial cells)-specific issue. We have established a mouse model in which specific ablation of BRCA1 as well as p53 genes occurred in the mammary epithelial cells by WAP promoter. The short latency, complete penetrance and similarity with human breast etiology make this mouse model very valuable. Interestingly, concomitantly with the inactivation of Brca1, expression of progesterone receptors (PR) was significantly enhanced. Consistently, treatment of these mice with the anti-progesterone, mifepristone (RU486), significantly delays or prevents mammary tumorigenesis. This observation provides a potential application to prevent BRCA1-carrier from breast tumorigenesis by treating with anti-progesterone. However, the complication of RU486 and the molecular mechanism of this effect remain to be addressed. Two specific aims are proposed;Aim 1. To determine the efficacy of the new anti-progesterone, CDB-2914, in preventing Brca1/p53-associated mammary carcinogenesis by determination of the optimal dose and developmental window required for maximal efficacy, investigation of the prevention mechanism of CDB-2914 and comparing with RU486. Furthermore, we plan to explore the potential of CDB-2914 in blocking tumor recurrence after chemotherapeutic treatment. Aim 2 is to elucidate the detailed mechanism of how BRCA1 modulates PR expression by testing whether PR ubiquitination is primed by GSK-3? phosphorylation and investigating the biological effects of ubiquitin-deficient as well as phosphorylation deficient PR on cell proliferation and refractory to BRCA1 regulation. We expect that results obtained from this proposal will make important contributions to the future prevention and treatment of breast cancer. PUBLIC HEALTH RELEVANCE: Our long-term goals are to understand why mammary epithelial cells harboring BRCA1 mutations are more sensitive to progesterone exposure and to determine whether a new anti- progesterone is effective as a single agent for preventing or delaying breast cancer development in high risk women. How the progesterone receptor activity is regulated will be studied. The results will provide insights into breast cancer intervention and will have important implications for in breast cancer prevention and treatment.